Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients.

Abstract

PURPOSE:

Tumor antigen-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)-mediated cytotoxicity. However, the role of CD8(+) CTL and FcγR in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging.

EXPERIMENTAL DESIGN:

FcγRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated patients with head and neck cancer (HNC). Flow cytometry was carried out to quantify EGF receptor (EGFR)-specific T cells in cetuximab-treated patients with HNC. The effect of cetuximab on natural killer (NK) cell, dendritic cell (DC), and T-cell activation was measured using IFN-γ release assays and flow cytometry.

RESULTS:

FcγRIIIa polymorphism did not predict clinical outcome in cetuximab-treated patients with HNC; however, elevated circulating EGFR(853-861)-specific CD8(+) T cells were found in cetuximab-treated patients with HNC (P < 0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR(+) tumor cells and FcγRIIIa on NK cells but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-γ-dependent expression of DC maturation markers, antigen processing machinery components such as TAP-1/2 and T-helper cell (T(H)1) chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK cell-induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another tumor antigen, MAGE-3.

CONCLUSION:

Cetuximab-activated NK cells promote DC maturation and CD8(+) T-cell priming, leading to tumor antigen spreading and TH1 cytokine release through "NK-DC cross-talk." FcγRIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK-DC interaction and mAb-induced cross-presentation. EGFR-specific T cells in cetuximab-treated patients with HNC may contribute to clinical response.

• Authors: Raghvendra M Srivastava, Steve C Lee, Pedro A Andrade Filho, Christopher A Lord, Hyun-Bae Jie, H Carter Davidson, Andrés López-Albaitero, Sandra P Gibson, William E Gooding, Soldano Ferrone, Robert L Ferris
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 7 Pg. 1858-72 (Apr 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23444227 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2013 AACR.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP-Binding Cassette Transporters
• Antibodies, Monoclonal, Humanized
• Antigens, Neoplasm
• Cytokines
• FCGR3A protein, human
• KLRK1 protein, human
• NK Cell Lectin-Like Receptor Subfamily K
• Receptors, IgG
• TAP1 protein, human
• Interferon-gamma
• ErbB Receptors
• Cetuximab

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Aged
• Antibodies, Monoclonal, Humanized (immunology, therapeutic use)
• Antibody-Dependent Cell Cytotoxicity (immunology)
• Antigens, Neoplasm (immunology)
• Cell Line, Tumor
• Cetuximab
• Coculture Techniques
• Cross-Priming (immunology)
• Cytokines (biosynthesis)
• Dendritic Cells (immunology, metabolism)
• ErbB Receptors (immunology)
• Female
• Genotype
• Head and Neck Neoplasms (drug therapy, genetics, immunology, mortality, pathology)
• Humans
• Interferon-gamma (metabolism)
• Killer Cells, Natural (immunology, metabolism)
• Lymphocyte Activation
• Male
• Middle Aged
• NK Cell Lectin-Like Receptor Subfamily K (metabolism)
• Neoplasm Staging
• Polymorphism, Genetic
• Receptor Cross-Talk (immunology)
• Receptors, IgG (genetics, immunology)
• T-Lymphocytes (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Th1 Cells (immunology, metabolism)